Background

Mesenchymal stromal cells (MSCs, “adult stem cells”) have been widely used experimentally in a variety of clinical contexts. There is interest in using these cells in critical illness, however, the safety profile of these cells is not well known. We thus conducted a systematic review of clinical trials that examined the use MSCs to evaluate their safety.

Methods and Findings

MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (to June 2011), were searched. Prospective clinical trials that used intravascular delivery of MSCs (intravenously or intra-arterially) in adult populations or mixed adult and pediatric populations were identified. Studies using differentiated MSCs or additional cell types were excluded. The primary outcome adverse events were grouped according to immediate events (acute infusional toxicity, fever), organ system complications, infection, and longer term adverse events (death, malignancy). 2347 citations were reviewed and 36 studies met inclusion criteria. A total of 1012 participants with clinical conditions of ischemic stroke, Crohn's disease, cardiomyopathy, myocardial infarction, graft versus host disease, and healthy volunteers were included. Eight studies were randomized control trials (RCTs) and enrolled 321 participants. Meta-analysis of the RCTs did not detect an association between acute infusional toxicity, organ system complications, infection, death or malignancy. There was a significant association between MSCs and transient fever.

Conclusions

Based on the current clinical trials, MSC therapy appears safe. However, further larger scale controlled clinical trials with rigorous reporting of adverse events are required to further define the safety profile of MSCs.

BACKGROUND

Pulmonary embolism is a common condition. Some patients subsequently develop chronic thromboembolic pulmonary hypertension (CTEPH). Many care gaps exist in the diagnosis and management of CTEPH patients including lack of awareness, incomplete diagnostic assessment, and inconsistent use of surgical and medical therapies.

METHODS

A representative interdisciplinary panel of medical experts undertook a formal clinical practice guideline development process. A total of 20 key clinical issues were defined according to the patient population, intervention, comparator, outcome (PICO) approach. The panel performed an evidence-based, systematic, literature review, assessed and graded the relevant evidence, and made 26 recommendations.

RESULTS

Asymptomatic patients postpulmonary embolism should not be screened for CTEPH. In patients with pulmonary hypertension, the possibility of CTEPH should be routinely evaluated with initial ventilation/ perfusion lung scanning, not computed tomography angiography. Pulmonary endarterectomy surgery is the treatment of choice in patients with surgically accessible CTEPH, and may also be effective in CTEPH patients with disease in more ‘distal’ pulmonary arteries. The anatomical extent of CTEPH for surgical pulmonary endarterectomy is best assessed by contrast pulmonary angiography, although positive computed tomography angiography may be acceptable. Novel medications indicated for the treatment of pulmonary hypertension may be effective for selected CTEPH patients.

CONCLUSIONS

The present guideline requires formal dissemination to relevant target user groups, the development of tools for implementation into routine clinical practice and formal evaluation of the impact of the guideline on the quality of care of CTEPH patients. Moreover, the guideline will be updated periodically to reflect new evidence or clinical approaches.

Background

Patient registries are commonly used to track survival and medical outcomes in large cohorts. However, large-scale collection of health-related quality of life (HRQOL) data is more challenging because such data must be collected directly from patients. Internet-based HRQOL questionnaires are a potential solution, allowing home data collection with immediate storage in a central database.

Objectives

Our objectives were to investigate the sociodemographic predictors of Internet use and willingness to convey HRQOL information over the Internet in a Canadian tertiary care patient population and to determine whether Internet use patterns of tertiary care patients differ from those of the general Canadian population. Additionally, we sought to identify the success of home completion of Internet-based HRQOL questionnaires, as well as factors hindering home completion.

Methods

We surveyed 644 patients at the Toronto General and St. Michael’s Hospitals from November 2003 through July 2006 within a prospective, longitudinal cohort study of HRQOL in patients with lung disease or lung transplants. Using multiple logistic regression, we assessed patient age, gender, rurality, marital status, and employment or education status as potential sociodemographic predictors of having an Internet-accessible home computer, using email at least weekly, and willingness to complete a quality of life questionnaire over the Internet. Patients electing to complete questionnaires over the Internet were followed from September 2005 through March 2008 to assess completion of HRQOL questionnaires from home, identify barriers for noncompletion, and determine sociodemographic predictors for home completion.

Results

Of the 644 patients, the median age was 51 years, with a similar number of males and females. Most were urban Ontario residents, were unemployed, and were married or in a common-law relationship. Having an Internet-accessible home computer was reported by 79.7% (513/644) of patients and use of email at least weekly by 66.5% (414/623) of patients. A majority of patients (57.1% 368/644) were willing to complete HRQOL questionnaires over the Internet via an emailed link. Of the participating 644 patients, 368 elected to complete future questionnaires from home and, as part of a gradual roll-out of the home HRQOL questionnaire, 211 were sent emails inviting them to do so. Of the invited patients, 78% (165/211) completed at least one questionnaire from home. The most common reason for noncompletion was a lack of or an inability to find time to complete the questionnaire. No statistically significant sociodemographic predictors of Internet use were associated with completion or noncompletion of questionnaires from home.

Conclusions

Home, Internet-based HRQOL assessment is feasible in tertiary care patient populations with a high predicted rate of Internet usage based on sociodemographic parameters. A large minority of patients were unwilling or unable to take part in home HRQOL assessments indicating that alternative methods of data collection are still required. However, the majority of patients electing to complete home HRQOL assessments went on to do so over the Internet.

Introduction

Patients with intracranial hemorrhage due to traumatic brain injury are at high risk of developing venous thromboembolism including deep vein thrombosis (DVT) and pulmonary embolism (PE). Thus, there is a trade-off between the risks of progression of intracranial hemorrhage (ICH) versus reduction of DVT/PE with the use of prophylactic anticoagulation. Using decision analysis modeling techniques, we developed a model for examining this trade-off for trauma patients with documented ICH.

Methods

The decision node involved the choice to administer or to withhold low molecular weight heparin (LMWH) anticoagulation prophylaxis at 24 hours. Advantages of withholding therapy were decreased risk of ICH progression (death, disabling neurologic deficit, non-disabling neurologic deficit), and decreased risk of systemic bleeding complications (death, massive bleed). The associated disadvantage was greater risk of developing DVT/PE or death. Probabilities for each outcome were derived from natural history studies and randomized controlled trials when available. Utilities were obtained from accepted databases and previous studies.

Results

The expected value associated with withholding anticoagulation prophylaxis was similar (0.90) to that associated with the LMWH strategy (0.89). Only two threshold values were encountered in one-way sensitivity analyses. If the effectiveness of LMWH at preventing DVT exceeded 80% (range from literature 33% to 82%) our model favoured this therapy. Similarly, our model favoured use of LMWH if this therapy increased the risk of ICH progression by no more than 5% above the baseline risk.

Conclusions

Our model showed no clear advantage to providing or withholding anticoagulant prophylaxis for DVT/PE prevention at 24 hours after traumatic brain injury associated with ICH. Therefore randomized controlled trials are justifiable and needed to guide clinicians.

BACKGROUND:

The Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) is the first disease-specific instrument for assessing patient-reported symptoms, functioning and quality of life (QoL) in pulmonary arterial hypertension (PAH).

OBJECTIVES:

To create and validate French-Canadian (FC) and English-Canadian (EC) language versions of the CAMPHOR.

METHODS:

A translation panel (for the FC version) and lay panels (for both versions) were convened to adapt the questionnaires (dual-panel methodology). Subsequently, these new questionnaires were field-tested in 15 FC PAH and 15 EC PAH patients. Finally, in a postal validation study, the new language versions of the CAMPHOR underwent psychometric evaluation in 41 FC and 52 EC PAH patients to test for reliability and validity.

RESULTS:

The FC and EC field-test interview participants found the questionnaires relevant, comprehensible and easy to complete. Psychometric analyses showed that the FC and EC adaptations were successful. High test-retest coefficients for the scales after controlling for change in respondent’s QoL (FC: 0.92 to 0.96; EC: 0.85 to 0.99) indicated a high degree of reliability. The FC and EC CAMPHOR scales had good internal consistency (Cronbach’s alpha coefficients 0.90 to 0.92 and 0.88 to 0.92, respectively). Predicted correlations with the Nottingham Health Profile provided evidence of the construct validity of the FC and EC scales. The FC and EC adaptations also showed known groups validity.

CONCLUSIONS:

The FC and EC adaptations of the CAMPHOR have been shown to be reliable and valid for measures of health-related QoL and QoL in PAH, and thus can be recommended for use in clinical studies and routine practice in PAH.

Background

Critically ill patients with renal insufficiency are predisposed to both deep vein thrombosis (DVT) and bleeding. The objective of the present study was to evaluate the prevalence, incidence and predictors of DVT and the incidence of bleeding in intensive care unit (ICU) patients with estimated creatinine clearance <30 ml/min.

Methods

In a multicenter, open-label, prospective cohort study of critically ill patients with severe acute or chronic renal insufficiency or dialysis receiving subcutaneous dalteparin 5,000 IU once daily, we estimated the prevalence of proximal DVT by screening compression venous ultrasound of the lower limbs within 48 hours of ICU admission. DVT incidence was assessed on twice-weekly ultrasound testing. We estimated the incidence of major and minor bleeding by daily clinical assessments. We used Cox proportional hazards regression to identify independent predictors of both DVT and major bleeding.

Results

Of 156 patients with a mean (standard deviation) creatinine clearance of 18.9 (6.5) ml/min, 18 had DVT or pulmonary embolism within 48 hours of ICU admission, died or were discharged before ultrasound testing – leaving 138 evaluable patients who received at least one dose of dalteparin. The median duration of dalteparin administration was 7 days (interquartile range, 4 to 12 days). DVT developed in seven patients (5.1%; 95% confidence interval, 2.5 to 10.1). The only independent risk factor for DVT was an elevated baseline Acute Physiology and Chronic Health Evaluation II score (hazard ratio for 10-point increase, 2.25; 95% confidence interval, 1.03 to 4.91). Major bleeding developed in 10 patients (7.2%; 95% confidence interval, 4.0 to 12.8), all with trough anti-activated factor X levels ≤ 0.18 IU/ml. Independent risk factors for major bleeding were aspirin use (hazard ratio, 6.30; 95% confidence interval, 1.35 to 29.4) and a high International Normalized Ratio (hazard ratio for 0.5-unit increase, 1.68; 95% confidence interval, 1.07 to 2.66).

Conclusion

In ICU patients with renal insufficiency, the incidence of DVT and major bleeding are considerable but appear related to patient comorbidities rather than to an inadequate or excessive anticoagulant from thromboprophylaxis with dalteparin.

Clinical Trial Registration

Number NCT00138099.

BACKGROUND

It has long been debated whether patients with atrial septal defect (ASD) Eisenmenger syndrome have idiopathic pulmonary arterial hypertension with an incidental ASD or severe pulmonary hypertension on the basis of their ASD shunt magnitude alone.

HYPOTHESIS

It was hypothesized that if ASD Eisenmenger patients had idiopathic pulmonary arterial hypertension with an incidental ASD, a mutation in the bone morphogenetic protein receptor-2 (BMPR2) would be found in some of these patients.

PATIENTS AND METHODS

All adult patients with ASD Eisenmenger syndrome were identified from the databases of two adult congenital cardiac units, and were matched to a control group with similar types of ASDs and no pulmonary hypertension. Gene coding for BMPR2 was examined for mutation using denaturing high-performance liquid chromatography of the entire coding sequence.

RESULTS

Eighteen adult patients with ASD Eisenmenger syndrome and 18 control patients were identified. ASD Eisenmenger patients had significantly larger ASDs than the control patients (3.7±1.2 cm versus 1.9±0.7 cm, P<0.01). A mutation in BMPR2 was not detected in either group.

CONCLUSION

ASD Eisenmenger syndrome may occur without BMPR2 mutation. Whether shunt magnitude alone or in combination with yet another genetic mutation is responsible for the development of pulmonary hypertension in these patients remains to be determined.

BACKGROUND:

Bosentan has been shown to be a safe and efficacious treatment for idiopathic pulmonary arterial hypertension (PAH) and PAH associated with connective tissue disease. However, there are limited studies examining the benefits of bosentan in PAH associated with congenital heart disease (CHD).

OBJECTIVE:

The aim of the present pilot study was to explore the safety and efficacy of bosentan in patients with PAH associated with CHD.

PATIENTS AND METHODS:

In the present study, 11 patients with PAH associated with CHD were enrolled to receive bosentan for a minimum of 16 weeks (62.5 mg twice a day for four weeks; thereafter 125 mg twice a day). Safety was assessed by monitoring adverse events, oxygen saturation, systemic blood pressure, pulse, complete blood count and liver function tests. Efficacy was assessed by the World Health Organization functional class, 6 min walk test (6-MWT), modified Borg dyspnea index, echocardiography and the 36-item short form health survey.

RESULTS:

Ten patients completed the 16-week treatment period (one patient withdrew). Bosentan was not associated with a deterioration in resting oxygen saturation (83.0±4.6% at week 16 versus 81.9±6.1% at baseline; P=0.402), or a deterioration in post-6-MWT oxygen saturation (70.1±10.9% at week 16 versus 68.7±15.1% at baseline; P=0.747). Two patients experienced three serious adverse events. The distance walked in 6 min improved significantly by 28 m (P=0.005) at week 16 compared with baseline, and the modified Borg dyspnea index also improved at week 16 compared with baseline (P=0.050). The World Health Organization functional class improved from class III to class II for five of 10 patients (50%). Patients’ self-rated quality of life (36-item short form health survey) demonstrated a non-significant improvement in each of the eight domains. Obtaining reliable echocardiographic measurements was difficult. Most echocardiographic parameters were only measurable on few patients, and none were measured on all patients, questioning the usefulness of echocardiography as a measuring tool for patients with complex CHD.

CONCLUSION:

Bosentan was not associated with worsening of resting oxygen saturation or exercise systemic oxygen saturation, suggesting its potential as a safe treatment option for patients with PAH associated with CHD. Improved 6-MWT and the modified Borg dyspnea index also suggested the possibility of bosentan as an efficacious treatment option for these patients. The results of the present study provide evidence for the need and feasibility of a large randomized, placebo-controlled clinical trial.

Objective To review the literature on the use of inhaled nitric oxide to treat acute lung injury/acute respiratory distress syndrome (ALI/ARDS) and to summarise the effects of nitric oxide, compared with placebo or usual care without nitric oxide, in adults and children with ALI or ARDS.

Design Systematic review and meta-analysis.

Data sources Medline, CINAHL, Embase, and CENTRAL (to October 2006), proceedings from four conferences, and additional information from authors of 10 trials.

Review methods Two reviewers independently selected parallel group randomised controlled trials comparing nitric oxide with control and extracted data related to study methods, clinical and physiological outcomes, and adverse events.

Main outcome measures Mortality, duration of ventilation, oxygenation, pulmonary arterial pressure, adverse events.

Results 12 trials randomly assigning 1237 patients met inclusion criteria. Overall methodological quality was good. Using random effects models, we found no significant effect of nitric oxide on hospital mortality (risk ratio 1.10, 95% confidence interval 0.94 to 1.30), duration of ventilation, or ventilator-free days. On day one of treatment, nitric oxide increased the ratio of partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2 ratio) (13%, 4% to 23%) and decreased the oxygenation index (14%, 2% to 25%). Some evidence suggested that improvements in oxygenation persisted until day four. There was no effect on mean pulmonary arterial pressure. Patients receiving nitric oxide had an increased risk of developing renal dysfunction (1.50, 1.11 to 2.02).

Conclusions Nitric oxide is associated with limited improvement in oxygenation in patients with ALI or ARDS but confers no mortality benefit and may cause harm. We do not recommend its routine use in these severely ill patients.

Introduction

We conducted this study to evaluate the feasibility of implementing an internet-linked handheld computer procedure logging system in a critical care training program.

Methods

Subspecialty trainees in the Interdepartmental Division of Critical Care at the University of Toronto received and were trained in the use of Palm handheld computers loaded with a customized program for logging critical care procedures. The procedures were entered into the handheld device using checkboxes and drop-down lists, and data were uploaded to a central database via the internet. To evaluate the feasibility of this system, we tracked the utilization of this data collection system. Benefits and disadvantages were assessed through surveys.

Results

All 11 trainees successfully uploaded data to the central database, but only six (55%) continued to upload data on a regular basis. The most common reason cited for not using the system pertained to initial technical problems with data uploading. From 1 July 2002 to 30 June 2003, a total of 914 procedures were logged. Significant variability was noted in the number of procedures logged by individual trainees (range 13–242). The database generated by regular users provided potentially useful information to the training program director regarding the scope and location of procedural training among the different rotations and hospitals.

Conclusion

A handheld computer procedure logging system can be effectively used in a critical care training program. However, user acceptance was not uniform, and continued training and support are required to increase user acceptance. Such a procedure database may provide valuable information that may be used to optimize trainees' educational experience and to document clinical training experience for licensing and accreditation.

Introduction

Outside the intensive care unit (ICU), clinically important deep vein thrombosis (DVT) is usually defined as a symptomatic event that leads to objective radiologic confirmation and subsequent treatment. The objective of the present survey is to identify the patient factors and radiologic features of lower limb DVT that intensivists consider more or less likely to make a DVT clinically important in ICU patients.

Methods

Our definition of clinically important DVT was a DVT likely to result in short-term or long-term morbidity or mortality if left untreated, as opposed to a DVT that is unlikely to have important consequences. We asked respondents to indicate the likelihood that patient factors and ultrasonographic features make a DVT clinically important using a five-point scale (from 1 = much less likely to 5 = much more likely).

Results

Of the 71 Canadian intensivists who responded, 70 (99%) rated three patient factors as most likely to make a DVT clinically important: clinical suspicion of pulmonary embolism (mean score 4.6), acute or chronic cardiopulmonary morbidity that might limit a patient's ability to tolerate pulmonary embolism (score 4.5), and leg symptoms (score 4.2). Of the ultrasound features, proximal (score 4.7), large (score 4.2), and totally occlusive (score 3.9) thrombi were considered the three most important.

Conclusion

When labeling a DVT as clinically important, intensivists rely on different patient specific factors and thrombus characteristics than are used to assess the clinical importance of DVT outside the ICU. The clinical importance of DVT is influenced by unique factors such as cardiopulmonary reserve among mechanically ventilated patients.

Vasopressin is emerging as a rational therapy for vasodilatory shock states. In part 1 of the review we discussed the structure and function of the various vasopressin receptors. In part 2 we discuss vascular smooth muscle contraction pathways with an emphasis on the effects of vasopressin on ATP-sensitive K+ channels, nitric oxide pathways, and interaction with adrenergic agents. We explore the complex and contradictory studies of vasopressin on cardiac inotropy and coronary vascular tone. Finally, we summarize the clinical studies of vasopressin in shock states, which to date have been relatively small and have focused on physiologic outcomes. Because of potential adverse effects of vasopressin, clinical use of vasopressin in vasodilatory shock should await a randomized controlled trial of the effect of vasopressin's effect on outcomes such as organ failure and mortality.

Vasopressin is emerging as a rational therapy for vasodilatory shock states. Unlike other vasoconstrictor agents, vasopressin also has vasodilatory properties. The goal of the present review is to explore the vascular actions of vasopressin. In part 1 of the review we discuss structure, signaling pathways, and tissue distributions of the classic vasopressin receptors, namely V1 vascular, V2 renal, V3 pituitary and oxytocin receptors, and the P2 class of purinoreceptors. Knowledge of the function and distribution of vasopressin receptors is key to understanding the seemingly contradictory actions of vasopressin on the vascular system. In part 2 of the review we discuss the effects of vasopressin on vascular smooth muscle and the heart, and we summarize clinical studies of vasopressin in shock states.